Waldenstrom's macroglobulinemia (WM) is a relatively rare post-germinal center lymphoplasmacytic tumor that secretes large amounts of IgM. Although WM has some similarities to lymphoplasmacytic lymphoma and multiple myeloma, very little is known about the molecular pathogenesis of WM. We have initiated the following studies. First, we have obtained the only putative WM cell line (WSU-WM) and have studied it by: molecular karyotypic analyses; molecular characterization of a t(8;14) translocation that dysregulates c-myc; determination of mutations in expressed mu and c-myc; and lymphochip microarray analysis of genes expressed in this line. Second, we have developed the technology to purify and characterize WM tumor cells, with a major focus of using FISH to detect aneuploidy of specific chromosomes plus translocations involving IgH and IgL loci. Preliminary results indicate that IgH switch recombination and IgH translocations are rare in WM, which together with the pleotropic lymphoplasmacytic morphology suggest that a block to IgH switching and plasma cell differentiation may contribute to the pathogenesis of this tumor. Third, we are developing strategies that may enable us to immortalize WM tumor cells. Fourth, we are collaborators in a treatment protocol to which patients with WM have been added. Finally, we are also collaborators in a chemoprevention protocol for MGUS, including IgM MGUS that can represent a premalignant stage of WM. We will also be analyzing the MGUS samples for karyotypic abnormalities as described above when this protocol begins, hopefully early in 2001.